The microbiome in autoinflammatory diseases: a missing link?

We are not alone. Right now, there are over 500 species of bacteria living in your mouth. Each part of your gut (stomach, small intestine, large intestine) provides a home to 1000 unique bacterial species. There are many more bacteria living on your skin and in every orifice in your body. Microbes make up (at least half of) who we are. We are a walking ecosystem with an incredible diversity of organisms unique to us, and in more ways than one, they make up who we are and what we do.

This “cloud” of microbes that lives in and on us (called the “microbiome”) provides essential functions for our well-being. Microbes help to digest our food, produce valuable nutrients, and prevent the growth of “bad” bacteria from harming us. In exchange, we provide the bacteria with a warm, humid, protected place to live. What a deal!

Let’s look at familial Mediterranean fever (FMF), the most common inherited autoinflammatory disease. In medical school, I learned that FMF is a genetic disease that requires inheriting two mutated copies of the MEFV (MEditerranean FeVer) gene. However, this theory does not fully explain what I actually see in practice. First, there are many patients with FMF that have only one mutated gene –and some patients with FMF have no mutated genes at all! Second, if FMF is a genetic disease, and you always carry the faulty genes with you, why does it often take many years for patients to develop their first symptoms of FMF? Third, what triggers the attacks, and what makes them go away? Finally, why is the severity of FMF is dependent on the country where you live?

It is possible that the microbiome helps to explain some of these differences. Researchers have known for years that if you are an Armenian with FMF living in Armenia, your disease is more severe than if you were living in the US. Similarly, a Turkish patient living in Turkey has more severe disease than a Turkish patient in Germany.

More recently, researchers have also shown that the country where you live helps to determine the composition of your microbiome: if you live in Venezuela, for example, you will have a different microbiome than if you lived in Vermont. Your microbiome also changes as you age.

An interesting theory from mice

Last month, a study of autoinflammatory disease in mice showed a remarkable effect of diet and the microbiome on disease severity. These mice inherit two mutated copies of a gene that cause a disease similar to the human autoinflammatory disease chronic recurrent multifocal osteomyelitis. When fed a normal low-fat diet, all mice develop the disease. However, researchers found that if they instead feed the mice a high-fat diet, it changes their microbiome and they don’t get sick! In addition, by transferring bacteria between healthy and diseased mice (via a fecal transplant), researchers could “give” the disease to some mice, while “protecting” others.

In these mice, it seems that diet determines the variety of bacteria that grow in the gut, and this mix of bacteria determines how much inflammation is produced in the gut, which in turn determines whether the mice will develop the disease.

What this study shows is that even though the mice were genetically determined to develop an autoinflammatory disease, whether or not they actually developed the disease depended on their diet, and in turn, on their gut microbiome.

It remains to be seen whether diet and the microbiome can have such powerful effects on the severity of human autoinflammatory diseases such as FMF.

What do you think? Have you noted that your diet or country of residence influenced the severity of your autoinflammatory disease?

Interested in seeing how I wrote this essay? Take a look at my Slow TV video to find out exactly how it was done!

I would also note that this mouse genetic disease was created in a lab and is not found in nature. This mutation has not been found to cause CRMO in humans, and there is still research being done to find the cause of this disease in people. This study got a lot of attention, but more research is needed to determine if this diet for the mice would work for other such diseases, or in humans. But it gives us a lot to think about!

Karen, thanks for your thoughtful comments. The genetics of this mouse are quite interesting. The mice are homozygous for a mutation in the Pstpip1 gene, which is the homologue of the human PSTPIP1 gene that causes PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne). Ironically, the mice with this mutation don’t develop any of the PAPA symptoms, and humans with PSTPIP1 mutations don’t develop osteomyelitis. You’re absolutely right that neither this gene (nor any other) has been implicated in the development of human chronic multifocal osteomyelitis.

I think this study, if nothing else, has raised a fundamental question that bears serious consideration. Dietary issues have been overlooked in the study of FMF, while genetics have increasingly dominated the research agenda. Genetics clearly do not explain everything. They do not explain why symptoms can start at almost any age in a person with FMF mutations. Many genetic disorders require an environmental factor to become symptomatic. When the issue of FMF triggers (of acute symptoms) is raised, the question of dietary triggers is usually not raised. In fact, even patients may not recognize their own dietary triggers. There is a characteristic delay between an FMF trigger and its consequential inflammatory symptoms – usually from 24-72 hours. So if a trigger-food is eaten every day, the association between trigger and FMF event will not be apparent. In this way food triggers have remained hidden to both doctors and patients. But when FMF patients begin to alter the consumption of trigger foods by eliminating it for a few days and then reintroducing it the trigger can be easily observed. Dairy (cow’s milk) and gluten are frequent triggers for FMF patients. Dietary changes to avoid trigger foods are an unrecognized opportunity for improved symptom control in FMF. One more point. The mouse study discussed here was in a genetically altered mouse and raises questions about whether the study findings would relate to humans. There is a naturally occurring animal model for FMF – it is the Shar Pei breed of dog. The veterinary specialist in Shar Pei pathology states that diet is an important factor in the Shar Pei treatment protocol and that the dogs are prone to food intolerances. The dogs are put on a grain-free diet, and supplements of fish oil and a probiotic are added. The possibility that the gastrointestinal environment, as a frontline barrier to the systemic immune system, might be a contributor to the inflammatory mechanism in auto-inflammatory diseases seems worthy of consideration.
Janine Jagger

Janine, you brought up some excellent points. I think we can learn a lot about medical diseases from our veterinary colleagues (this TED talk by Natterson-Horowitz shows us how: http://drha.us/1IxjKAg). In addition, I agree that it’s possible the role of genetics in “genetic” diseases such as FMF may be overemphasized. Clearly they are not sufficient to explain what actually happens to patients. Further research is needed on the role of diet, the microbiome, and autoinflammatory diseases.